Cardiac insufficiency or cardio-circulatory failure is a major health problem. Classical therapy for many years has relied upon the use of cardiac glycosides and diuretics. More recently peripheral vasodilators also have been used.
Many patients do not respond, however, to these therapies and, as a consequence, pharmacological treatment of cardiac failure is still considered unsatisfactory, requiring therefore a search for new cardioactive drugs which are able to act on the main pathogenetic factors of the cardiocirculatory failure, namely a decrease of myocardial contractility and impairment in peripheral blood flow.
2-Amino tetrahydronaphthalene derivatives (alternatively named as 2-aminotetraline) exhibit interesting pharmacological properties because of their capacity of binding to the different receptors of the orthosympathetic system. The 5,6- and 6,7-dihydroxy derivatives of 2-aminotetraline contain, in particular, the dopamine moiety fixed in a semirigid structure which has in recent years given rise to considerable research effort.
A number of such 2-amino-tetrahydronaphthalenes are known. Gorczynski et al., J. Med. Chem., 1981, 24, 835-839 disclose 2-[1-(4-hydroxyphenyl)-but-3-ylamino]-6,7-dihydroxy-1,2,3,4-tetrahydronaph thalene.
EP-A-209275 and EP-A-273017 disclose 2-amino-6,7-dihydroxytetralin in derivatives.
EP-A-211721 disclose 2-aminotetralin compounds having lipolytic activity.
GB-A-2123410 discloses 2-amino-5,6-dihydroxytetralin derivatives having Beta- stimulating adrenergic activity.
Dopaminergic drugs can have different therapeutic uses. Drugs stimulating the post-synaptic dopamine receptors in the central nervous system (CNS) may be effective against Parkinson's disease. Drugs acting as agonists of dopamine autoreceptors, always in the CNS, may be used as antipsychotics.
Dopaminergic receptors, however, also are present on the peripheral sympathetic terminations so that much research effort recently has been directed to dopaminergic structures having peripheral cardiovascular activity.
There are a number of structure-activity studies of 2-aminotetraline derivatives giving rise to different hypothesis on the importance and effects of, for example, the configuration of the C.sub.2 carbon, the optimal substitution on the amine, the kind and number of substituents on the aromatic ring, and changes of other parameters. From these studies, however, it is evident that 2-aminotetralines are rather heterogeneous as far as their pharmacological effects and their mechanism of action are concerned, the latter involving, both central and peripheral dopaminergic receptors and alpha and beta adrenergic receptors.
As with other classes of sympathicomimetics, even very small structural differences can result in remarkable effects on the degree and/or kind of activity, depending on various interdependent factors such as the kind and position of substituents, conformation, interactions with the receptor site, metabolic pathway.